Molecular docking is now routinely used as a method in virtual screening for lead compound generation and optimization. A limitation of docking into a single protein conformation for virtual screening is that ignoring protein flexibility will reduce predictive power. Many molecular docking algorithms have been optimized for fast and accurate docking of a flexible ligand into a static protein structure. Therefore, an attractive approach to incorporate protein flexibility is to use a small number of representative protein structures for rigid docking. For a test set of 12 proteins, several conformational sampling techniques will be used to generate representative protein ensembles for molecular docking. The results of rigid docking into multiple crystal structures will be compared against rigid docking into generated protein ensembles. These results will be used to develop a new algorithm that directly incorporates protein flexibility into the docking procedure with torsion angle dynamics. In virtual screening, the potential benefits of including protein flexibility (fewer false negatives) would be diminished if flexibility also leads to a higher false positive rate. To investigate this issue, many ligands known to bind to our target proteins with low affinity will also be included in our study.